US6750203B1 - Product derived from milk substantially free of beta casein from non-human mammals and relative use - Google Patents

Product derived from milk substantially free of beta casein from non-human mammals and relative use Download PDF

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US6750203B1
US6750203B1 US09/095,639 US9563998A US6750203B1 US 6750203 B1 US6750203 B1 US 6750203B1 US 9563998 A US9563998 A US 9563998A US 6750203 B1 US6750203 B1 US 6750203B1
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pro
ile
seq
beta
gly
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US09/095,639
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Paolo Pozzilli
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Mead Johnson Nutrition Co
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Midia Ltd
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Assigned to MIDIA LIMITED reassignment MIDIA LIMITED ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: POZZILLI, PAOLO
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Assigned to BRISTOL-MYERS SQUIBB COMPANY reassignment BRISTOL-MYERS SQUIBB COMPANY ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: MIDIA LIMITED
Assigned to MJN RESTRUCTURING HOLDCO, INC. reassignment MJN RESTRUCTURING HOLDCO, INC. ASSIGNMENT OF ASSIGNORS INTEREST (SEE DOCUMENT FOR DETAILS). Assignors: BRISTOL-MYERS SQUIBB COMPANY
Assigned to MEAD JOHNSON NUTRITION COMPANY reassignment MEAD JOHNSON NUTRITION COMPANY MERGER (SEE DOCUMENT FOR DETAILS). Assignors: MJN RESTRUCTURING HOLDCO, INC.
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/46—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates
    • C07K14/47—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals
    • C07K14/4701—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans from vertebrates from mammals not used
    • C07K14/4732—Casein
    • A—HUMAN NECESSITIES
    • A23—FOODS OR FOODSTUFFS; TREATMENT THEREOF, NOT COVERED BY OTHER CLASSES
    • A23L—FOODS, FOODSTUFFS, OR NON-ALCOHOLIC BEVERAGES, NOT COVERED BY SUBCLASSES A21D OR A23B-A23J; THEIR PREPARATION OR TREATMENT, e.g. COOKING, MODIFICATION OF NUTRITIVE QUALITIES, PHYSICAL TREATMENT; PRESERVATION OF FOODS OR FOODSTUFFS, IN GENERAL
    • A23L33/00—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof
    • A23L33/10—Modifying nutritive qualities of foods; Dietetic products; Preparation or treatment thereof using additives
    • A23L33/17—Amino acids, peptides or proteins
    • A23L33/19—Dairy proteins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • A61P3/08—Drugs for disorders of the metabolism for glucose homeostasis
    • A61P3/10—Drugs for disorders of the metabolism for glucose homeostasis for hyperglycaemia, e.g. antidiabetics
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10—TECHNICAL SUBJECTS COVERED BY FORMER USPC
    • Y10S—TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
    • Y10S530/00—Chemistry: natural resins or derivatives; peptides or proteins; lignins or reaction products thereof
    • Y10S530/827—Proteins from mammals or birds
    • Y10S530/832—Milk; colostrum

Definitions

  • the present invention is related to a product derived from milk substantially free of beta casein from non-human mammals.
  • the invention is also related to the use of such a product especially in terms of its application in relation to diet, particularly for early infancy, in the prevention of insulin-dependent diabetes.
  • casein in basic terminology represents a group of proteins obtainable by milk precipitation at acid pH and up to room temperature, specifically pH 4.6 and 20° C. Caseins represent approximately 80% of total cow's milk proteins and 40% p/v human milk. Casein can be sub-divided into three main groups: alpha, beta and kappa. There is also a fourth group, represented by gamma casein, which is derived from beta casein following the removal of the first twenty-two amino acids. Therefore, for the present invention, gamma casein will be considered as part of beta casein.
  • Beta casein represents approximately 70% p/v of all casein present in human milk, whereas in cow's milk, it represents approximatly 25% p/v.
  • bovine beta casein several genetic variants are known and have been characterized, including A1, A2, A3, B, C, D and E.
  • A1 For the industrial production of milk, mainly the genetic variant of milk A1 has been favored to increase the amount of milk produced.
  • This variant which contains more proteins than others, has been obtained from various selected animals, in particular cows.
  • the amino acid sequence in position 63-68 has been identified for cow's beta casein A1, corresponding to the 54-59 sequence of human beta casein. A similar situation has been discovered with regard to the variant A2.
  • Both variants A1 and A2 of beta casein also show sequence homology in that region (at least 90 percent) with a specific protein of insulin-producing cells in the pancreas (GLUT2).
  • the sequence 63-68 of A1 and A2 beta casein and, more generally, the analogue sequences of other types of casein, such as A1, A2, A3, B, C, D and E elicit an immune response via production of anti beta casein antibodies and lymphocytes which recognize such sequences.
  • the present invention is related to a product derived from milk or milk itself, substantially free of non-human beta casein with immunogenic characteristic as specified in prior art.
  • Another object of the invention is a milk-derived product or milk itself comprising al least one beta casein modified from non-human mammals witout the immunogenic characteristic mentioned above.
  • Another object of the invention is the use of such a product, in relation to diet.
  • Another object of the invention is the use of a product from milk or milk itself, substantially free of non-human mammals beta casein in order to obtain a food for the early infant diet for the prevention of insulin-dependent diabetes.
  • Pro-Gly-Pro-Ile-His -Asn (where the underlined sequence is SEQ ID NO:1) for the A1 beta casein inserted in the larger fragment: Ser-Leu-Val-Tyr-Pro-Phe- Pro-Gly-Pro-Ile-His -Asn (SEQ ID NO:3).
  • Beta casein from bos indicus (63-68); Pro-Gly-Pro-Ile-Pro -Asn (underlined sequence SEQ ID NO:2).
  • human beta casein has the following sequence (48-59): Ser-Leu-Val-Tyr-Pro-Phe- Val-Glu-Pro-Ile-Pro- Tyr (SEQ ID NO:6).
  • the peptide fraction relevant to the present invention has been identified as (54-59): Val-Glu-Pro-Ile-Pro -Tyr (where the underlined sequence is SEQ ID NO:5).
  • the peptide sequences of GLUT2, the glucose transporter inside insulin-producing beta cells in the pancreas, are the following:
  • the inventor suggests that the sequence of A1, B and C beta casein and gamma casein, Pro-Gly-Pro-Ile-His (SEQ ID NO:1), and the larger fragments containing it, such as the sequences of beta casein A2, A3 and E. Pro-Gly-Pro-Ile-Pro (SEQ ID NO:2), are responsible for the induction of an immune response towards beta casein which, by cross reactivity, would be directed towards the homologous sequence of GLUT2, causing damage to the cells that produce insulin.
  • beta casein does not contain such a sequence (e.g., it has been removed)
  • beta casein is modified in that such a sequence is substituted with a sequence of human beta casein;
  • the milk obtained comprising casein modified as stated above, can be administered as such or can be treated with known methods, as the casein(s) involved can be separated and used to produce food and pharmaceutical products.
  • the products including such casein can be used for adiministration in early infancy and later on as a diet for the prevention of insulin-dependent diabetes.
  • concentrations of A1 and/or A2 and/or other immunogenic beta caseins in particular those with the sequence Pro-Gly-Pro-Ile-His (SEQ ID NO:1) or Pro-Gly-Ile-Pro (SEQ ID NO:2), do not represent more than 10% b.w. of the final product.
  • the food products of the invention can be, for instance, pasta, milk and milk-derived products and proteins, such as those added to food, all of which are already in the marketplace, the modification being the substitution of the immunogenic caseins with the caseins of the present invention.
  • Also part of the present invention are vegetable and/or synthetic proteins, such as those derived from soya.
  • vegetable and/or synthetic proteins such as those derived from soya.
  • a food product or a milk according to the following alternatives:
  • beta casein is lower than 10% b.w. or the beta casein comprising the amino acid sequence Gly-Pro-Ile-His (SEQ ID NO:7) or Gly-Pro-Ile-Pro (SEQ ID NO:8) is lower than 10% by w.
  • beta casein comprising the amino acid sequence Gly-Pro-Ile-His (SEQ ID NO:7) or Gly-Pro-Ile-Pro (SEQ ID NO:8) and integrated with peptides derived from the hydrolysis of animal, vegetable and/or synthetic proteins, and lacking these above sequences and mixtures thereof (FR 86-00325, WO94/06306, WO p (02539));
  • beta casein comprising the amino acid sequence Gly-Pro-Ile-His (SEQ ID NO:7) or Gly-Pro-Ile-Pro (SEQ ID NO:8) is lower than 10% b.w. and, integrated with peptides coming from hydrolisis of animal and/or vegetal and/or synthetic proteins lacking such sequences and mixtures thereof;
  • beta casein is lacking the amino acid sequence Gly-Pro-Ile-His (SEQ ID NO:7) or Gly-Pro-Ile-Pro (SEQ ID N0:8) in that it has been obtained from animal species genetically not producing proteins with such sequences;
  • milk comprising human beta casein obtained from genetically manipulated microorganisms or animals, such as those described in the above mentioned patent.
  • the protein fractions can be derived from chemical-physical treatments of milk and from lyophylized casein, for instance by differential solubility, liquid-liquid extraction, membrane separation, chromatographic separation, as described in patents FR 86-00325 and WO92/00017.
  • the integrations can be carried out by using recombinant beta casein produced with one of the well-known cloning methods, using yeat, bacteria, funghi or transgenic animals, such as those described in patent WO 93/04171.
  • a process for removing beta casein from milk is the chromatographic process, as described below.
  • beta casein is separated, starting from acid casein, and by means of chromatography in two steps, the remaining fractions of alpha and kappa casein will be obtained.
  • the process can be optimized using the knowledge already available in the field.
  • Such a process includes the use, as basic phase, of a resin of ionic exchange, for example Sepharose® from Pharmacia, with the concentration also in columns.
  • the mobile phase is constituted by Buffer A:
  • the acid casein can be dissolved in Buffer A at pH not less than 6, with the addition of a specific reducing agent, DTT, (Ditiotreeitol).
  • DTT a specific reducing agent
  • the mixture should be left under for 24 hours, brought to pH between 5 and 6 and placed in columns.
  • the beta casein fraction does not interact with the resin and is eluted in ⁇ M NaCl. It is not necessary, therefore, to carry out stages of, increasing ionic concentration, considering that the process at hand merely involves a simple separation of beta casein from the other fractions, which will be collected in isocratic by eluting with buffer B:
  • fractions are later dialfiltrated to eliminate urea and other salts; after concentration, caseins are collected by acid precipitation and the obtained wet product is lyophilized.
  • FIG. 1 is the chromatogram relating to the initial load of Example 1;
  • FIG. 2 illustrates a chromatographic peack relating to the beta casein
  • FIG. 3 refers to the absence of the beta casein in the chromatogram.
  • beta casein Separation of beta casein from acid casein and collection of the remaining alpha and kappa casein fractions.
  • Casein should be slowly dissolved in the buffer, keeping pH 7 with 2M NaOH at each addition.
  • Resin S-Sepharose Pharmacia height 85 cm, volume 1670 ml
  • All buffers are filtrated by using a Millex pre-filter AP 50 bound in series with filter 0.45 ⁇ m Millipak 20 (Millipore).
  • Example 1 The product of Example 1 has been purified from urea by the following method of diafiltration.
  • Buffer of dialysis demineralized water sodium acetate 10 mM ph?7 ionic strength 0.8 mS total volume 250 l (5 washes)
  • the lyophilization is carried out on the product free of urea, by using a Christ model Beta 1-16 equipment.

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  • Health & Medical Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Medicinal Chemistry (AREA)
  • Engineering & Computer Science (AREA)
  • Diabetes (AREA)
  • General Health & Medical Sciences (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Biochemistry (AREA)
  • Toxicology (AREA)
  • Mycology (AREA)
  • Nutrition Science (AREA)
  • Genetics & Genomics (AREA)
  • Food Science & Technology (AREA)
  • Polymers & Plastics (AREA)
  • Biophysics (AREA)
  • Emergency Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Endocrinology (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
  • Peptides Or Proteins (AREA)
  • Dairy Products (AREA)
  • Coloring Foods And Improving Nutritive Qualities (AREA)
  • Medicines Containing Material From Animals Or Micro-Organisms (AREA)
  • Feed For Specific Animals (AREA)
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US09/095,639 1995-12-27 1996-12-27 Product derived from milk substantially free of beta casein from non-human mammals and relative use Expired - Lifetime US6750203B1 (en)

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US10/793,111 US7091320B2 (en) 1995-12-27 2004-03-04 Product derived from milk substantially free of beta casein from non-human mammals and relative use

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ITRM95A0850 1995-12-27
IT95RM000850A IT1277964B1 (it) 1995-12-27 1995-12-27 Prodotto derivato da latte, sostanzialmente esente da betacaseina di mammifero non umano e relativo uso
PCT/EP1996/005846 WO1997024371A1 (en) 1995-12-27 1996-12-27 Product derived from milk substantially free of beta casein from non-human mammals and relative use

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EP (1) EP0871662B1 (it)
AT (1) ATE207079T1 (it)
AU (1) AU720411B2 (it)
BR (1) BR9612346A (it)
CA (1) CA2241171C (it)
DE (1) DE69616088T2 (it)
ES (1) ES2164938T3 (it)
IT (1) IT1277964B1 (it)
NO (1) NO314383B1 (it)
NZ (1) NZ325826A (it)
WO (1) WO1997024371A1 (it)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060265768A1 (en) * 1995-05-16 2006-11-23 Mclachlan Corran Norman Stuart Breeding and milking cows for milk free of beta-casein A1
US20080132454A1 (en) * 2004-02-26 2008-06-05 Arjian Geerlings Antihypertensive Peptides

Families Citing this family (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
GB9912852D0 (en) * 1999-06-02 1999-08-04 Regen Therapeutics Plc Peptides
GB0029777D0 (en) * 2000-12-06 2001-01-17 Regen Therapeutics Plc Peptides
EP2270133B1 (en) * 2008-04-22 2015-06-24 Corporación Alimentaria Peñasanta (Capsa) Method for obtaining a novel strain of bifidobacterium bifidum with activity against infection by helicobacter pylori
WO2010119088A2 (en) * 2009-04-15 2010-10-21 Bodo Melnik Milk and milk-based products modified to exhibit a reduced insulinemic index and/or reduced mitogenic activity
US8889633B2 (en) 2013-03-15 2014-11-18 Mead Johnson Nutrition Company Nutritional compositions containing a peptide component with anti-inflammatory properties and uses thereof
US9352020B2 (en) 2013-03-15 2016-05-31 Mead Johnson Nutrition Company Reducing proinflammatory response
US9138455B2 (en) 2013-03-15 2015-09-22 Mead Johnson Nutrition Company Activating adiponectin by casein hydrolysate
US9289461B2 (en) 2013-03-15 2016-03-22 Mead Johnson Nutrition Company Reducing the risk of autoimmune disease
JP2022531390A (ja) * 2019-05-02 2022-07-06 ニュー カルチャー インコーポレイテッド チーズおよびヨーグルト様組成物ならびに関連する方法
US11771105B2 (en) 2021-08-17 2023-10-03 New Culture Inc. Dairy-like compositions and related methods

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US4501585A (en) * 1982-08-23 1985-02-26 Friedman Laura L Mother's milk harvesting and collection device
WO1991008675A1 (en) 1989-12-20 1991-06-27 Slattery Charles W Human infant formulas containing recombinant human alpha-lactalbumin and beta-casein
WO1992000017A1 (fr) 1990-06-25 1992-01-09 Eurial Procede et dispositif pour l'obtention de caseine beta
US5084285A (en) * 1989-06-01 1992-01-28 Snow Brand Milk Products, Co., Ltd. Desalting process of milk
WO1993004171A1 (en) 1991-08-19 1993-03-04 Symbicom Aktiebolag Human beta-casein, process for producing it and use thereof
US5304489A (en) * 1987-02-17 1994-04-19 Genpharm International, Inc. DNA sequences to target proteins to the mammary gland for efficient secretion
US5643880A (en) * 1994-05-26 1997-07-01 Abbott Laboratories Product for inhibition of attachment of H. influenzae to human cells

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FR2650955B1 (fr) * 1989-08-16 1992-01-10 Agronomique Inst Nat Rech Procede d'obtention, a partir de la caseine beta, de fractions enrichies en peptides a activite biologique et les fractions peptidiques obtenues
WO1994006306A1 (en) * 1992-09-22 1994-03-31 New Zealand Dairy Board A process for producing beta-casein enriched products
FR2714390B1 (fr) * 1993-12-23 1996-03-08 Agronomique Inst Nat Rech Procédé d'obtention de produits peptidiques et produits obtenus.
DE69536000D1 (de) * 1994-11-04 2009-10-22 A2 Corp Ltd Selektionsverfahren für nicht-diabetogene milch oder milchprodukte sowie hierdurch erfasste milch oder milchprodukte
ATE297125T1 (de) * 1995-05-16 2005-06-15 A2 Corp Ltd Nahrungsmittel und herstellungsverfahren

Patent Citations (9)

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US4501585A (en) * 1982-08-23 1985-02-26 Friedman Laura L Mother's milk harvesting and collection device
US5304489A (en) * 1987-02-17 1994-04-19 Genpharm International, Inc. DNA sequences to target proteins to the mammary gland for efficient secretion
US5084285A (en) * 1989-06-01 1992-01-28 Snow Brand Milk Products, Co., Ltd. Desalting process of milk
WO1991008675A1 (en) 1989-12-20 1991-06-27 Slattery Charles W Human infant formulas containing recombinant human alpha-lactalbumin and beta-casein
US5795611A (en) * 1989-12-20 1998-08-18 Slattery; Charles W. Human infant formulas containing recombinant human alpha-lactalbumin and beta-casein
WO1992000017A1 (fr) 1990-06-25 1992-01-09 Eurial Procede et dispositif pour l'obtention de caseine beta
US5397577A (en) * 1990-06-25 1995-03-14 Eurial - Parc Club Du Perray Method for obtaining beta casein
WO1993004171A1 (en) 1991-08-19 1993-03-04 Symbicom Aktiebolag Human beta-casein, process for producing it and use thereof
US5643880A (en) * 1994-05-26 1997-07-01 Abbott Laboratories Product for inhibition of attachment of H. influenzae to human cells

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Atkinson et. al.; Type 1 diabetes: new perspectives on disease pathogensis and treatment, 2001, The Lancet, vol. 358: 221-229.* *
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Cavallo et. al.; Cell-mediated immune response to B casein in recent-onset insulin-dependent diabetes: implications for disease pathogenesis, 1996, The Lancet, vol. 348: 926-928.* *
Chianese et al (Lait 73(5-6): 533-547, abstract only, 1993.* *
Tullin et al, A pronounced thymic B cell deficiency in the spontaneously diabetic BB rat 1 pp. 5554-5559 1997. *

Cited By (5)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20060265768A1 (en) * 1995-05-16 2006-11-23 Mclachlan Corran Norman Stuart Breeding and milking cows for milk free of beta-casein A1
US7563575B2 (en) * 1995-05-16 2009-07-21 A2 Corporation Limited Breeding and milking cows for milk free of β-casein A1
US20100041042A1 (en) * 1995-05-16 2010-02-18 A2 Corporation Limited Breeding and milking cows for milk free of beta-casein a1
US7863002B2 (en) 1995-05-16 2011-01-04 A2 Corporation Limited Breeding and milking cows for milk free of β-casein A1
US20080132454A1 (en) * 2004-02-26 2008-06-05 Arjian Geerlings Antihypertensive Peptides

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WO1997024371A1 (en) 1997-07-10
DE69616088D1 (de) 2001-11-22
BR9612346A (pt) 1999-12-28
NO982777L (no) 1998-06-16
CA2241171C (en) 2007-11-13
EP0871662A1 (en) 1998-10-21
ITRM950850A0 (it) 1995-12-27
NZ325826A (en) 2000-05-26
US7091320B2 (en) 2006-08-15
EP0871662B1 (en) 2001-10-17
ES2164938T3 (es) 2002-03-01
AU1306697A (en) 1997-07-28
NO982777D0 (no) 1998-06-16
AU720411B2 (en) 2000-06-01
IT1277964B1 (it) 1997-11-12
DE69616088T2 (de) 2002-08-01
CA2241171A1 (en) 1997-07-10
ATE207079T1 (de) 2001-11-15
NO314383B1 (no) 2003-03-17
US20050176638A1 (en) 2005-08-11
ITRM950850A1 (it) 1997-06-27

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